The homopentameric a7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel (Papke, R. L. (2014) Biochem. Pharmacol.) characterized by a unique form of concentration-dependent rapid desensitization (Papke, & Papke (2002) Br. J. Pharm. 137: 49-61; Papke & Thinschmidt (1998) Neurosci. Let. 256: 163-166). The receptor belongs to the large superfamily of ligand-gated ion channels (Papke, R. L. (2014) Biochem. Pharmacol.) that are all characterized by a disulfide-constrained “Cys-loop”, which is thought to be involved in the conformational changes linking ligand binding and ion channel activation.
Nicotinic acetylcholine receptors (nAChRs) are validated therapeutic targets for several pathologies of the central and peripheral nervous system including Alzheimer's and Parkinson's diseases, addiction disorders, schizophrenia, pain management, and inflammation-mediated processes. Recent reports have provided evidence for expression of this receptor subtype in non-neuronal cells including lymphocytes, macrophages, and intestinal and lung endothelial and epithelial cells (Parrish et al., (2008) Mol. Med. 14: 567-574; Rosas-Ballina et al., (2009) Mol. Med. 15: 195-202; Al-Wadei et al., (2012) Mol. Cancer Res. 10: 239-249; Matteoli et al., (2014) Gut 63: 938-948), indicating a non-synaptic role for the receptor. Moreover, α7 is a key part of the cholinergic anti-inflammatory response (Wang et al., (2003) Nature 421: 384-388) in which levels of pro-inflammatory cytokines are decreased (Tracey, K. J. (2007) J. Clin. Invest. 117: 289-296), making this receptor of great interest considering the wide range of diseases in which systemic inflammation is present.
Further, nicotine and other αagonists (Saeed et al., (2005) J. Exp. Med. 201: 1113-1123) have been effective in models of inflammation, inhibiting local leukocyte recruitment and reducing endothelial cell activation, implicating α7 nAChR involvement in regulation of inflammatory processes. All these data makes the α7 receptor a promising drug target for the treatment of several neurological disorders including inflammatory diseases and chronic pain. Notably, anti-inflammatory effects has been associated with desensitized, non-conducting states of the receptor (Thomsen & Mikkelsen (2012) J. Neuroimmunol. 251: 65-72; Papke et al., (2015) NeuroPharm. 91: 34-42). Thus, compounds that are able to selectively place the receptor into a desensitized state rather than act as partial agonists are of considerable interest (Papke et al., (2015) NeuroPharm. 91: 34-42). For the α7 receptor two distinct desensitized states have been identified (Williams et al., (2011) Mol. Pharmacol. 80: 1013-1032). They differ in being sensitive (Ds) or insensitive (Di) to conversion to open states by a type II PAM. Silent agonists are desensitizing compounds that have been identified and designed to selectively induce the Ds state in the α7 nAChR with extremely low or absent partial agonist activity. The archetype compound 1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl) phenyl) furan-2-yl) methanone (NS6740), lacking in the ability to generate an α7 ion current, is an example of a silent agonist associated with anti-inflammatory activity; however, even the simple tetraethyl ammonium cation is a silent agonist for the α7 nAChR (Papke et al., (2015) NeuroPharm. 91: 34-42; Chojnacka et al., (2013) Bioorg. Med. Chem. Lett. 23: 4145-4149).
It was recently reported that the compound N,N-diethyl-N′-phenyl piperazine (diEPP) (Papke et al., (2014) J. Pharmacol. Experimental Therap. 350: 665-680) is also active as a silent agonist, and it has a structure that lends itself well to functionalization to explore the potential for further enhancement and control of silent agonist activity.